During the past year, we have completed extensive analyses of the National Comorbidity Survey - Replication (NCS-R) data and have published numerous papers on the following topics: bipolar disorder with frequent mood episodes;bipolar spectrum disorder;the association between mood and anxiety disorder and vascular diseases and risk factors;mental disorders as risk factors for later substance dependence;examine socio-demographic predictors of transitions across drug use stages to improve targets for the prevention of drug use disorders;Associations between the order of drug use initiation and the development of drug dependence. We investigated the prevalence and correlates of a surrogate measure of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) rapid cycling BPD from NCS-R (Nierenberg et al, 2009). Virtually nothing is known about the epidemiology of rapid cycling bipolar disorder (BPD) in community samples. BPD with frequent mood episodes (FME) in NCS R was associated with younger age-of-onset (of bipolar 1 disorder (BP-I), but not bipolar 2 disorder (BP-II)) and higher annual persistence (73% of the years since first onset of illness with an episode) than non-FME BPD. No substantial associations of FME vs non-FME BPD were found with socio-demographics, childhood risk factors (parental mental disorders, other childhood adversities) or comorbid DSM-IV disorders. However, FME manic episodes had greater clinical severity than non-FME episodes (assessed with a fully structured version of the Young Mania Rating Scale) and FME hypomanic episodes had greater role impairment than non-FME episodes (assessed with the Sheehan Disability Scales). Whether these indicators of severity merely reflect attenuated effects of rapid cycling or independent effects of sub-threshold rapid cycling warrants further study given the high proportion of lifetime cases who met criteria for FME. We also conducted analyses on the spectrum concept of mood disorders using a dimensional framework to characterize people with mania and/or depression (Angst et al, in press). This work is being conducted with a team of international investigators who propose to modify the current diagnostic nomenclature by considering bipolar disorder and major depression as a spectrum of symptoms, duration, recurrence, and severity rather than as discrete categories. Our findings clearly confirm the validity of the spectrum concept in a general population sample based on independent indices such as disability, impairment, family history, severity and patterns of comorbidity. We assessed the association between mood and anxiety disorders with vascular diseases and risk factors using NCS-R data (Fedorowicz et al, ). Our results indicate vascular disease was associated with bipolar disorder in women, and major depressive disorder in men. When adjusted for anxiety disorders in examining the association between vascular disease and mood disorders, the association between mood disorder and vascular disease was attenuated but remained statistically significant for mania and hypomania, but not for major depressive disorder in women, and the association between major depression and vascular disease became non-significant in men. The independence of the associations between mood disorders and vascular disease from the well-established cardiovascular risk factors (diabetes mellitus, family history of heart disease, high blood pressure, smoking, and obesity) suggests the need for future research into physiological mechanisms by which vascular disease may be linked to mood or anxiety disorders. The sex differences in the links between vascular diseases and mood disorders, particularly bipolar disorder, should also stimulate further study to elucidate mechanisms for this important association. We compared the prevalence and correlates of the full spectrum of DSM-IV bipolar disorder in a series of nationally representative surveys from 11 countries using common methodology. Despite the differences in prevalence rates across countries, nearly 90% of those with lifetime BPI or BPII disorder also meet criteria for another lifetime disorder, and 70% of those with bipolar spectrum disorders have a history of three or more disorders. The findings demonstrate that the rates of bipolar disorder are fairly consistent worldwide, and confirm the dramatic impact and severity of this condition. The unmet need for services for bipolar disorder, particularly in low income countries is alarming (Merikangas et al). We examined the risk posed by comorbid psychopathology for the onset of substance use disorders and whether it would be cost-effective to prevent secondary substance dependence by large-scale interventions aimed at index mental disorders. The findings of these investigations demonstrate that, despite their frequent role in the onset of substance abuse and dependence, treating index mental disorders as a means reducing substance dependence would not be cost-effective relative to other prevention options. However, prevention of substance dependence might be considered an important secondary outcome of interventions for early-onset mental disorders. We have examined the role of pre-existing mental disorders and socio-demographics in explaining the predictive effects of violations using data from NCS R. The 'gateway'pattern of drug initiation describes a normative sequence, beginning with alcohol and tobacco use, followed by cannabis, then other illicit drugs. The findings indicate for the first time that drug use initiation follows a strong normative pattern, deviations from which are not strongly predictive of later problems. By contrast, adolescents who have already developed mental health problems are at risk for deviations from the normative sequence of drug initiation and for the development of dependence. Other work in progress includes evaluation of the role of migraine, sleep disorder, family and marital factors, childhood abuse and neglect in clinical severity, disability, comorbidity and service use for mental disorder from NCS R data; Latent class analysis on bipolar spectrum disorder to investigate whether it is dimensional or categorical. We also examine prospectively on bipolar spectrum disorder using NCS-baseline (1990) and NCS-II (2000) panel data. Public Health Impact: These investigations expand our knowledge on the magnitude and correlates of bipolar spectrum disorder and its relation to depressive disorder;they provide highly novel information concerning the precise stages of the substance use trajectory that are most associated with population-based risk factors, knowledge that has direct implications for improving the precision of selective and indicated prevention strategies.